US4619922A - 6α, 16α-dimethyl corticoids - Google Patents

6α, 16α-dimethyl corticoids Download PDF

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US4619922A
US4619922A US06/688,134 US68813485A US4619922A US 4619922 A US4619922 A US 4619922A US 68813485 A US68813485 A US 68813485A US 4619922 A US4619922 A US 4619922A
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group
dione
dimethyl
pregnene
hydroxy
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Klaus Annen
Henry Laurent
Helmut Hofmeister
Michael Topert
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
    • C07J7/0055—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group

Definitions

  • This invention relates novel 6,16-dimethyl corticoids, to pharmaceutical preparations containing them, and to compounds utilized as intermediates for their synthesis.
  • the present invention is 6 ⁇ ,16 ⁇ -dimethyl corticoids of general Formula I ##STR2## wherein the bond is a single bond or a double bond and
  • X is a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom
  • R 1 is a formyl group, an alkanoyl group or alkoxyalkyl group of 2-8 carbon atoms, or a benzoyl group, and
  • Y is a hydrogen atom, a chlorine atom, a hydroxy group, a formyl group, an alkanoyloxy group of 2-8 carbon atoms, or a benzyloxy group.
  • the present invention includes compounds of the general Formula VI ##STR3## wherein R 1 and Y have the meanings indicated for Formula I, Z is a hydrogen atom or a trifluoroacetoxy group, and wherein R 4 and R 5 jointly represent a methylene group or two hydrogen atoms, useful in the preparation of compounds of Formula I.
  • the present invention also contemplates pharmaceutical compositions containing the compounds of Formula I.
  • the novel 6,16-dimethyl corticoids of Formula I contain, as the substituent R 1 , a formyl group, a linear or branched alkanoyl or alkoxyalkyl group of 2-8 (preferably 2-6) carbon atoms, or a benzoyl group.
  • Suitable alkanoyl groups R 1 are, for example, the acetyl group, propionyl group, the butyryl group, the isobutyryl group, the valeryl group, the 3-methylbutyryl group, the trimethylacetyl group, or the hexanoyl groups.
  • alkoxyalkyl groups R 2 are alkoxymethyl groups, e.g. the methoxymethyl group, the ethoxymethyl group, the propoxymethyl group, the isopropoxymethyl group, the butoxymethyl group, the isobutoxymethyl group, or the tert-butoxymethyl group.
  • 6,16-dimethyl corticoids contain as the substituent Y a hydrogen atom, a chlorine atom, a hydroxy group, an alkanoyloxy group of 2-8 (preferably 2-6) carbon atoms, or a benzoyloxy group.
  • Suitable alkanoyloxy groups are, for example, those derived from the aforementioned alkanoyl groups.
  • the 6,16-dimethyl corticoids of general Formula I are distinguished by a pronounced anti-inflammatory activity when applied topically. Moreover, they show an excellent dissociation between desirable topical efficacy and undesirable systemic anti-inflammatory side effects.
  • the 6,16-dimethyl corticoids of general Formula I wherein X means a hydrogen atom, a fluorine atom, or a chlorine atom are more suited for use in pharmaceutical preparations than those wherein the substituent X represents a bromine atom, since the latter preparations are less stable in galenicals but nevertheless can be so used.
  • the 9-bromo steroids of general Formula I are valuable intermediates, using conventional methods, for the synthesis of the other 6,16-dimethyl corticoids of this invention having pharmacological efficacy.
  • novel 6,16-dimethyl corticoids of general Formula I are suited, in combination with the excipients customary in galenic pharmacy, for the local treatment of contact dermatitis, eczemas of a great variety of types, neurodermatoses, erythrodermia, burns, pruritus vulvae et ani, rosacea, erythematodes cutaneous, psoriasis, lichen ruber planus et verrucosus, and similar skin disorders.
  • the drug specialties are prepared in the usual way by converting the active agents together with suitable additives into the desired form of application, such as, for example: solutions, lotions, ointments, creams, or plasters.
  • suitable additives such as, for example: solutions, lotions, ointments, creams, or plasters.
  • the concentration of active ingredient is dependent on the form of application.
  • An active agent concentration of 0.001% to 1% is preferably utilized in lotions and ointments.
  • novel compounds are moreover readily suitable, optionally in combination with the usual excipients and auxiliary agents, also for the preparation of inhalants that can be employed for therapy of allergic diseases of the respiratory tract, for example bronchial asthma or rhinitis.
  • novel corticoids are furthermore also suitable, in the form of capsules, tablets, or dragees containing preferably 10-200 mg of active ingredient and being administered orally, or in the form of suspensions containing preferably 100-500 mg of active ingredient per dosage unit and being administered rectally, for the treatment of allergic diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
  • the present invention also relates to pharmaceutical preparations which contain a compound of Formula I.
  • the pharmacologically effective compounds of this invention can be processed by conventional methods of galenic pharmacy into pharmaceutical preparations for oral or parenteral administration, e.g., to mammals including humans.
  • Conventional excipients are pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or topical application which do not deleteriously react with the active compounds.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, polyethylene glycols, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy-methylcellulose, polyvinyl pyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • injectable sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including supporitories.
  • Ampoules are convenient unit dosages.
  • tablets, dragees, suppositories or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained released compositions can be formulated including those wherein the active compound is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • Suitable dosages and regimens for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compound and of a known agent, e.g., by means of an appropriate, conventional pharmacological protocol.
  • novel 6,16-dimethyl corticoids of the invention can be produced by opening, with hydrogen fluoride, the epoxy ring of a steroid of general Formula II ##STR4## wherein , R 1 and Y have the meanings given above or chemically adding hypochlorous or hypobromous acid to the ⁇ 9(11)-double bond of a steroid of general Formula III ##STR5## wherein , R 1 and Y have the meanings given in Formula I.
  • R 2 is an alkyl group of maximally 7 carbon atoms, or a phenyl group
  • R 3 is an alkyl group of 1-4 carbon atoms
  • the crude product is purified on silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 2.9 g of 21-acetoxy-17 ⁇ -hydroxy-16 ⁇ -methyl-6-methylene-11 ⁇ -trifluoroacetoxy-4-pregnene-3,20,-dione, mp 217°-219° C.
  • the crude product is purified on silica gel with a hexane-acetone gradient (0-40% acetone), thus isolating 1.05 g of 21-acetoxy-11 ⁇ -hydroxy-6 ⁇ ,16 ⁇ -dimethyl-17 ⁇ -propionyloxy-1,4-pregnadiene-3,20-dione, mp 182°-184° C.

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Abstract

6α,16α-Dimethyl corticoids of general Formula I ##STR1## wherein the bond is a single bond or a double bond,
X is a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom,
R1 is a formyl group, an alkanoyl group or alkoxyalkyl group of 2-8 carbon atoms, or a benzoyl group, and
Y is a hydrogen atom, a chlorine atom, a hydroxy group, a formyl group, an alkanoyloxy group of 2-8 carbon atoms, or a benzoyloxy group,
are pharmacologically effective compounds.

Description

BACKGROUND OF THE INVENTION
This invention relates novel 6,16-dimethyl corticoids, to pharmaceutical preparations containing them, and to compounds utilized as intermediates for their synthesis.
SUMMARY OF THE INVENTION
It is an object of this invention to provide new compounds having valuable pharmacological properties.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
In its composition aspect, the present invention is 6α,16α-dimethyl corticoids of general Formula I ##STR2## wherein the bond is a single bond or a double bond and
X is a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom,
R1 is a formyl group, an alkanoyl group or alkoxyalkyl group of 2-8 carbon atoms, or a benzoyl group, and
Y is a hydrogen atom, a chlorine atom, a hydroxy group, a formyl group, an alkanoyloxy group of 2-8 carbon atoms, or a benzyloxy group.
In another composition aspect, the present invention includes compounds of the general Formula VI ##STR3## wherein R1 and Y have the meanings indicated for Formula I, Z is a hydrogen atom or a trifluoroacetoxy group, and wherein R4 and R5 jointly represent a methylene group or two hydrogen atoms, useful in the preparation of compounds of Formula I.
The present invention also contemplates pharmaceutical compositions containing the compounds of Formula I.
DETAILED DISCUSSION
The novel 6,16-dimethyl corticoids of Formula I contain, as the substituent R1, a formyl group, a linear or branched alkanoyl or alkoxyalkyl group of 2-8 (preferably 2-6) carbon atoms, or a benzoyl group. Suitable alkanoyl groups R1 are, for example, the acetyl group, propionyl group, the butyryl group, the isobutyryl group, the valeryl group, the 3-methylbutyryl group, the trimethylacetyl group, or the hexanoyl groups. Especially worth mentioning as examples for alkoxyalkyl groups R2 are alkoxymethyl groups, e.g. the methoxymethyl group, the ethoxymethyl group, the propoxymethyl group, the isopropoxymethyl group, the butoxymethyl group, the isobutoxymethyl group, or the tert-butoxymethyl group.
These 6,16-dimethyl corticoids contain as the substituent Y a hydrogen atom, a chlorine atom, a hydroxy group, an alkanoyloxy group of 2-8 (preferably 2-6) carbon atoms, or a benzoyloxy group. Suitable alkanoyloxy groups are, for example, those derived from the aforementioned alkanoyl groups.
The 6,16-dimethyl corticoids of general Formula I are distinguished by a pronounced anti-inflammatory activity when applied topically. Moreover, they show an excellent dissociation between desirable topical efficacy and undesirable systemic anti-inflammatory side effects.
It is to be noted that the 6,16-dimethyl corticoids of general Formula I wherein X means a hydrogen atom, a fluorine atom, or a chlorine atom are more suited for use in pharmaceutical preparations than those wherein the substituent X represents a bromine atom, since the latter preparations are less stable in galenicals but nevertheless can be so used. However, on the other hand, the 9-bromo steroids of general Formula I are valuable intermediates, using conventional methods, for the synthesis of the other 6,16-dimethyl corticoids of this invention having pharmacological efficacy.
The novel 6,16-dimethyl corticoids of general Formula I are suited, in combination with the excipients customary in galenic pharmacy, for the local treatment of contact dermatitis, eczemas of a great variety of types, neurodermatoses, erythrodermia, burns, pruritus vulvae et ani, rosacea, erythematodes cutaneous, psoriasis, lichen ruber planus et verrucosus, and similar skin disorders.
The drug specialties are prepared in the usual way by converting the active agents together with suitable additives into the desired form of application, such as, for example: solutions, lotions, ointments, creams, or plasters. In the thus-formulated medical agents, the concentration of active ingredient is dependent on the form of application. An active agent concentration of 0.001% to 1% is preferably utilized in lotions and ointments.
The novel compounds are moreover readily suitable, optionally in combination with the usual excipients and auxiliary agents, also for the preparation of inhalants that can be employed for therapy of allergic diseases of the respiratory tract, for example bronchial asthma or rhinitis.
The novel corticoids are furthermore also suitable, in the form of capsules, tablets, or dragees containing preferably 10-200 mg of active ingredient and being administered orally, or in the form of suspensions containing preferably 100-500 mg of active ingredient per dosage unit and being administered rectally, for the treatment of allergic diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
The present invention also relates to pharmaceutical preparations which contain a compound of Formula I. The pharmacologically effective compounds of this invention can be processed by conventional methods of galenic pharmacy into pharmaceutical preparations for oral or parenteral administration, e.g., to mammals including humans. Conventional excipients are pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or topical application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, polyethylene glycols, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy-methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including supporitories. Ampoules are convenient unit dosages.
For enteral application, particularly suitable are tablets, dragees, suppositories or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained released compositions can be formulated including those wherein the active compound is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
Suitable dosages and regimens for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compound and of a known agent, e.g., by means of an appropriate, conventional pharmacological protocol.
The novel 6,16-dimethyl corticoids of the invention can be produced by opening, with hydrogen fluoride, the epoxy ring of a steroid of general Formula II ##STR4## wherein , R1 and Y have the meanings given above or chemically adding hypochlorous or hypobromous acid to the Δ9(11)-double bond of a steroid of general Formula III ##STR5## wherein , R1 and Y have the meanings given in Formula I.
and, if desired, eliminating the 9-positioned halogen atom from the 9-bromo steroids of general Formula I. dehydrogenating a steroid of general Formula I saturated in the 1,2-position, in this position. saponifying 21-acetoxy steroids of general Formula I. or esterifying 21-hydroxy steroids of general Formula I.
In an alternate process, 6,16-dimethyl corticoids of general Formula Ia ##STR6## wherein , X and Y have the meanings given in Formula I and
R2 is an alkyl group of maximally 7 carbon atoms, or a phenyl group,
are prepared by splitting the ortho ester of a steroid of general Formula IV ##STR7## wherein , X and R2 have the above meanings and
R3 is an alkyl group of 1-4 carbon atoms,
by means of acids, trimethylsilyl chloride, or triphenylmethyl chloride, or
rearranging a 21-acyl group of a steroid of general Formula V ##STR8## wherein , X and R2 have the above-indicated meanings,
and optionally esterifying a 21-positioned hydroxy group or exchanging same against hydrogen or chlorine, and optionally dehydrogenating a steroid saturated in the 1,2-position, in this position.
These processes can be carried out under the conditions as described in German Patent Applications Nos. P 26 45 105.8 and 28 03 661.5.
All of the starting materials required for the foregoing processes are known and/or readily preparable from known starting materials using fully conventional processes.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the following examples, all temperatures are set forth uncorrected in degrees Celsius. unless otherwise indicated, all parts and percentages are by weight.
EXAMPLE 1
(a) A solution of 30 g of 21-acetoxy-9α-fluoro-17α-hydroxy-16α-methyl-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione in 150 ml of methanol and 450 ml of tetrahydrofuran is hydrogenated with 15 g of tris(triphenyl)-phosphine rhodium(I) chloride at room temperature and under normal pressure for 20 hours. The mixture is concentrated to dryness under vacuum and the crude product is chromatographed on silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 24.8 g of 21-acetoxy-9α-fluoro-17α-hydroxy-16α-methyl-11β-trifluoroacetoxy-4-pregnene-3,20-dione, mp 248°-250° C.
(b) A suspension of 5 g of sodium acetate in 150 ml of chloroform and 150 ml of methylal is combined with 5 g of 21-acetoxy-9α-fluoro-17α-hydroxy-16α-methyl-11β-trifluoroacetoxy-4-pregnene-3,20-dione and, after adding 19 ml of phosphorus oxychloride dropwise, stirred for 4 hours at a bath temperature of 180° C. The reaction solution is neutralized with a saturated soda solution, the organic phase is separated and washed with water. After drying and concentrating, the crude product is purified on silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 2.9 g of 21-acetoxy-17α-hydroxy-16α-methyl-6-methylene-11β-trifluoroacetoxy-4-pregnene-3,20,-dione, mp 217°-219° C.
(c) 15 g of 21-acetoxy-17α-hydroxy-16α-methyl-6-methylene-11β-trifluoroacetoxy-4-pregnene-3,20-dione is dissolved in 225 ml of methanol and 15 ml of triethylamine. The mixture is stirred for 20 minutes at room temperature, concentrated under vacuum, and recrystallized from acetone/hexane, yielding 12.4 g of 21-acetoxy-9α-fluoro-11β,17α-dihydroxy-16α-methyl-6-methylene-4-pregnene-3,20-dione, mp 187°-189° C.
(d) Under heating, 12 g of 21-acetoxy-9α-fluoro-11β,17α-dihydroxy-16α-methyl-6-methylene-4-pregnene-3,20-dione is dissolved in 620 ml of isopropanol and, after adding 2.6 g of palladium/carbon (9.5% strength) and 36 ml of cyclohexene, agitated for 6 hours at a bath temperature of 110° C. Subsequently another 2 g of catalyst and 36 ml of cyclohexene are added, the mixture is further stirred for 20 hours, the reaction solution is suctioned off over "Celite" diatomaceous earth, thoroughly washed with methylene chloride, and concentrated to dryness under vacuum. The crude product is purified on silica gel with a hexane-ethyl acetate gradient (0-80% ethyl acetate), thus isolating 7.8 g of 21-acetoxy-9α-fluoro-11β,17α-dihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione, mp 204°-205° C.
(e) A solution of 5.2 g of 21-acetoxy-9α-fluoro-11β,17α-dihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione in 260 ml of methanol and 26 ml of water is agitated under argon with 1.3 g of potassium carbonate for 45 minutes at room temperature. After ice water precipitation, the product is worked up as usual, thus isolating 4.5 g of 9α-fluoro-11β,17α,21-trihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione, mp 242°-232° C.
(f) At a bath temperature of 130° C., about 24 ml of solvent is distilled off from the turbid mixture of 800 mg of 9α-fluoro-11β,17α,21-trihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione and 80 mg of pyridinium tosylate in 7 ml of dimethylformamide and 60 ml of hexane (cyclohexane). After a brief cooling-off period, 2 ml of triethyl orthoacetate is introduced into the warm solution and the remaining hexane (cyclohexane) is removed by distillation. Finally, the solution is combined with 0.8 ml of pyridine and concentrated under vacuum at 60° C., thus obtaining 17α,21-(1-ethoxyethylidene)-9α-fluoro-11β-hydroxy-6.alpha.,16α-dimethyl-4-pregnene-3,20-dione as an oil.
(g) A suspension of the crude 17α,21-(1-ethoxyethylidene)-9α-fluoro-11β-hydroxy-6.alpha.,16α-dimethyl-4-pregnene-3,20-dione in 24 ml of methanol is refluxed at 100° C. for one hour with a mixture of 0.96 ml of 0.1-molar aqueous sodium acetate solution and 8.5 ml of 0.1N aqueous acetic acid. The mixture is concentrated until turbid, poured on water, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness under vacuum. The crude product is purified on 65 g of silica gel with a hexane-acetone gradient (0-50% acetone).
Yield: 798 mg of 17α-acetoxy-9α-fluoro-11β,21-dihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione, mp 210°-211° C.
EXAMPLE 2
A solution of 650 mg of 17α-acetoxy-9α-fluoro-11β,21-dihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione in 6.5 ml of pyridine and 3.2 ml of acetic anhydride is stirred for 2 hours at room temperature and poured on an ice water-sodium chloride solution. The mixture is filtered off and worked up as usual. After crystallization from hexane/ethyl acetate, 430 mg of 17α,21-diacetoxy-9α-monofluoro-11β-hydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione is isolated, mp 194°-195° C.
EXAMPLE 3
(a) Analogously to Example 1(f), 500 mg of 9α-fluoro-11β-17α,21-trihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is reacted with 1.2 ml of triethyl orthopropionate to 17α,21-(1-ethoxypropylidenedioxy)-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione.
(b) The crude 17α,21-(1-ethoxypropylidenedioxy)-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is hydrolyzed under the conditions of Example 1(g), worked up, and purified, thus isolating 439 mg of 9α-fluoro-11β,21-dihydroxy-6α,16α-dimethyl-17.alpha.-propionyloxy-4-pregnene-3,20-dione, mp 195°-196° C.
EXAMPLE 4
Analogously to Example 2, 400 mg of 9α-fluoro-11β,21-dihydroxy-6α,16α-dimethyl-17.alpha.-propionyloxy-4-pregnene-3,20-dione is reacted with acetic anhydride to 312 mg of 21-acetoxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-17α-propionyloxy-4-pregnene-3,20-dione, mp 196°-198° C.
EXAMPLE 5
A solution of 500 mg of 17α,21-(1-ethoxypropylidenedioxy)-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione in 25 ml of dimethylformamide is stirred, after dropwise addition of 1 ml of trimethylchlorosilane, for 23 hours at a bath temperature of 80° C. After ice water precipitation and the usual working-up process, the crude product is purified on silica gel with a hexane-acetone gradient (0-30% acetone). Yield: 246 mg of 21-chloro-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-17.alpha.-propionyloxy-4-pregnene-3,20-dione, mp 258°-260° C.
EXAMPLE 6
(a) Under the conditions of Example 1(f), 1.0 g of 11β,17α,21-trihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is reacted with the ethyl ester of orthopropionic acid to 17α,21-(1-ethoxypropylidenedioxy)-11β-hydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione.
(b) The crude 17α,21-(1-ethoxypropylidenedioxy)-11β-hydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione is hydrolyzed analogously to Example 1(g), worked up, and purified, thus isolation 782 mg of 11β,21-dihydroxy-6α,16α-dimethyl-17α-propionyloxy-4-pregnene-3,20-dione.
(c) As described in Example 2, 500 mg of 11β,21-dihydroxy-6α,16α-dimethyl-17α-propionyloxy-4-pregnene-3,20-dione is reacted with acetic anhydride, worked up, and purified, thus obtaining 396 mg of 21-acetoxy-11β-hydroxy-6α,16α-dimethyl-17α-propionyloxy-4-pregnene-3,20-dione, mp 168°-170° C.
EXAMPLE 7
A solution of 2.0 g of 21-acetoxy-11β-hydroxy-6α,16α-dimethyl-17α-propionyloxy-4-pregnene-3,20-dione in 100 ml of dioxane is refluxed with 2.0 g of dichlorodicyanobenzoquinone for 24 hours. After cooling, the solid matter is suctioned off, washed with hexane, and the filtrate concentrated under vacuum. The crude product is purified on silica gel with a hexane-acetone gradient (0-40% acetone), thus isolating 1.05 g of 21-acetoxy-11β-hydroxy-6α,16α-dimethyl-17α-propionyloxy-1,4-pregnadiene-3,20-dione, mp 182°-184° C.
EXAMPLE 8
(a) A suspension prepared from 2.5 g of 9α-fluoro-11β,17α,21-trihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione and 250 mg of pyridinium toluenesulfonate in 100 ml of methyl tert-butyl ether ("Driveron" S) under argon. At an internal temperature of 58° C., 25 ml of "Driveron" S is distilled off, the mixture is cooled to 40° C., combined with 6 ml of the triethyl ester of orthobutyric acid, and subsequently refluxed for 2.5 hours so that no undissolved components are present. To this mixture is added 3 ml of pyridine and the solution is concentrated to form 17α,21-(1-ethoxybutylidenedioxy)-9α-fluoro-11β-hydroxy-6.alpha.,16α-dimethyl-4-pregnene-3,20-dione as an oil.
(b) The crude 17α,21-(1-ethoxybutylidenedioxy)-9α-fluoro-11β-hydroxy-6.alpha.,16α-dimethyl-4-pregnene-3,20-dione is hydrolyzed under the conditions of Example 1(g) to form 2.6 g of 17α-butyryloxy-9α-fluoro-11β,21-dihydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione, worked up, and purified, mp 166°-167° C.
EXAMPLE 9
As described in Example 2, 2.4 g of 17α-butyryloxy-9α-fluoro-11β,21-dihydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione in pyridine is reacted with 12 ml of acetic anhydride, worked up, and purified. Yield: 2.6 g of 21-acetoxy-17α-butyryloxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione, mp 181°-182° C.
EXAMPLE 10
Analogously to Example 7, 2.0 g of 21-acetoxy-17α-butyryloxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is dehydrated with 2.0 g of dichlorodicyanobenzoquinone, worked up, and purified, thus isolating 940 mg of 21-acetoxy-17α-butyryloxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-1,4-pregnadiene-3,20-dione, mp 229°-230° C.
EXAMPLE 11
(a) Under the conditions of Example 1(a), 1.4 g of 9α-fluoro-11β,17α,21-trihydroxy-6α,16α-dimethyl-4pregnene-3,20-dione is reacted with 3.4 ml of the triethyl ester of orthobenzoic acid to 17α,21-(1-ethoxybenzylidenedioxy)-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione as an oil.
(b) The crude 17α,21-(1-ethoxybenzylidenedioxy)-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is hydrolyzed under the conditions of Example 1(g), worked up, and purified, thus isolating 140 mg of 17α-benzoyloxy-9α-fluoro-11β,21-dihydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione as a foam.
EXAMPLE 12
(a) At 0° C., 1 ml of methanesulfonic acid chloride is added dropwise to a solution of 2.0 g of 17α-butyryloxy-9α-fluoro-11β,21-dihydroxy-6α,16.alpha.-dimethyl-4-pregnene-3,20-dione in 5 ml of pyridine. The mixture is further stirred for one hour at 0° C., poured on an ice water-sodium chloride solution, and worked up as usual, thus isolating 1.9 g of 17α-butyryloxy-9α-fluoro-11β-hydroxy-21-mesyloxy-6α,16α-dimethyl-4-pregnene-3,20-dione.
(b) A suspension of 1.9 g of 17α-butyryloxy-9α-fluoro-11β-hydroxy-21-mesyloxy-6α,16α-dimethyl-4-pregnene-3,20-dione and 1.9 g of lithium bromide in 40 ml of N-methylpyrrolidone is stirred for one hour at a bath temperature of 80° C. and worked up as usual. After chromatography on silica gel with a hexane-acetone gradient (0-30% acetone), 1.2 g of 21-bromo-17α-butyryloxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is isolated.
(c) 1.2 g of 21-bromo-17α-butyryloxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione in 30 ml of tetrahydrofuran is sitrred under argon with 7.5 ml of tributyltin hydride as well as a spatula tip of α,α'-azobisisobutyronitrile for 6 hours at 50° C. bath temperature. The mixture is then concentrated under vacuum and the residue chromatographed with a hexane-acetone gradient (0-25% acetone), thus isolating 920 mg of 17α-butyryloxy-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (11)

What is claimed is:
1. A 6α,16α-Dimethyl corticoid of the formula ##STR9## wherein the bond is a single bond or a double bond and
X is a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom,
R1 is a formyl group, an alkanoyl group or alkoxyalkyl group of 2-8 carbon atoms, or a benzoyl group, and
Y is a chlorine atom.
2. 21-Chloro-9α-fluoro-11β-hydroxy-6α,16α-dimethyl-17α-propionyloxy-4-pregnene-3,20-dione, a compound according to claim 1.
3. A compound of the formula ##STR10## wherein R1 is a formyl group, an alkanoyl group or alkoxyalkyl group of 2-8 carbon atoms, or a benzoyl group, and
Y is a hydrogen atom, a chlorine atom, a hydroxy group, a formyl group, an alkanoyloxy group of 2-8 carbon atoms, or a benzoyloxy group
Z is a hydrogen atom or a trifluoroacetoxy group,
and wherein R4 and R5 jointly represent a methylene group or two hydrogen atoms.
4. 21-Acetoxy-9.alpha.-fluoro-17-hydroxy-16α-methyl-11β-trifluoroacetoxy-4-pregnene-3,20-dione, a compound according to claim 3.
5. 21-Acetoxy-9α-fluoro-17-hydroxy-16.alpha.-methyl-6-methylene-11β-trifluoroacetoxy-4-pregnene-3,20-dione, a compound according to claim 3.
6. 21-Acetoxy-9α-fluoro-11β,17-dihydroxy-16α-methyl-6-methylene-4-pregnene-3,20-dione, a compound according to claim 3.
7. A pharmaceutical composition containing an effective antiinflammatory amount of one or two corticoids according to claim 1, and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition according to claim 7, adapted for topical administration.
9. A pharmaceutical composition according to claim 8 containing 0.001-1% by weight of corticoid.
10. A method for alleviating inflammation which comprises topically administering an anti-inflammatory effective amount of a compound according to claim 1 in a pharmaceutically acceptable carrier.
11. A 6α,16α-Dimethyl corticoid of the formula ##STR11## wherein the bond is a single bond or a double bond and
X is a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom,
R1 is alkoxyalkyl of 2-8 carbon atoms, and
Y is a hydrogen atom, a chlorine atom, a hydroxy group, a formyl group, an alkanoyloxy group of 2-8 carbon atoms, or a benzoyloxy group.
US06/688,134 1984-01-02 1985-01-02 6α, 16α-dimethyl corticoids Expired - Fee Related US4619922A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968822A (en) * 1987-12-11 1990-11-06 Taisho Pharmaceutical Co., Ltd. 21-alkoxysteroid compounds
US6835724B2 (en) * 1993-10-05 2004-12-28 Aventis Pharma Deutschland Gmbh Corticoid 17,21-dicarboxylic esters and corticosteroid 17-carboxylic ester 21-carbonic esters, processes for their preparation and pharmaceuticals containing these compounds
CN114057821A (en) * 2021-11-30 2022-02-18 黑龙江中医药大学 Preparation method of medroxyprogesterone acetate for perimenopausal syndrome

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60161914A (en) * 1984-02-02 1985-08-23 Green Cross Corp:The Steroid fatty acid ester-containing pharmaceutical preparation to be administered to rectum
DE3915951C1 (en) * 1989-05-12 1990-09-13 Schering Ag, 1000 Berlin Und 4709 Bergkamen, De
WO1995026974A1 (en) * 1994-04-04 1995-10-12 Meiji Milk Products Co., Ltd. Novel progesterone compound and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3054811A (en) * 1961-09-14 1962-09-18 Merck & Co Inc Ring a unsaturated 6, 16-dimethyl steroids of the pregnane series
US3312590A (en) * 1963-06-11 1967-04-04 Glaxo Lab Ltd Topically active anti-inflammatory 17-mono- and 17,21-diesters of betamethasone and its 9-chloro-analogs, compositions and use thereof
US4555507A (en) * 1982-07-19 1985-11-26 Schering Aktiengesellschaft Novel 6, 16-dimethylcorticoids, their preparation and use

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3004994A (en) * 1957-09-16 1961-10-17 Merck & Co Inc 6alpha, 16alpha-dimethyl-pregnenes
US3201429A (en) * 1958-07-12 1965-08-17 Syntex Corp 17, 21-diesters of 6alpha, 16alpha-dimethyl-delta4-pregnen-17alpha-21-diol-3, 20-dione and process therefor
GB898292A (en) * 1959-03-18 1962-06-06 Upjohn Co Improvements in or relating to steroids and the manufacture thereof
US3290338A (en) * 1959-06-01 1966-12-06 Schering Corp 16-alkylprogesterones and their 9alpha, 11beta-dihalogeno analogs
US3350426A (en) * 1962-06-14 1967-10-31 Syntex Corp 6alpha, 16alpha-dimethyl-1, 4-pregnadien-17alpha-ol-3, 20 dione and esters thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3054811A (en) * 1961-09-14 1962-09-18 Merck & Co Inc Ring a unsaturated 6, 16-dimethyl steroids of the pregnane series
US3312590A (en) * 1963-06-11 1967-04-04 Glaxo Lab Ltd Topically active anti-inflammatory 17-mono- and 17,21-diesters of betamethasone and its 9-chloro-analogs, compositions and use thereof
US4555507A (en) * 1982-07-19 1985-11-26 Schering Aktiengesellschaft Novel 6, 16-dimethylcorticoids, their preparation and use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968822A (en) * 1987-12-11 1990-11-06 Taisho Pharmaceutical Co., Ltd. 21-alkoxysteroid compounds
US6835724B2 (en) * 1993-10-05 2004-12-28 Aventis Pharma Deutschland Gmbh Corticoid 17,21-dicarboxylic esters and corticosteroid 17-carboxylic ester 21-carbonic esters, processes for their preparation and pharmaceuticals containing these compounds
CN114057821A (en) * 2021-11-30 2022-02-18 黑龙江中医药大学 Preparation method of medroxyprogesterone acetate for perimenopausal syndrome
CN114057821B (en) * 2021-11-30 2022-12-09 黑龙江中医药大学 Preparation method of medroxyprogesterone acetate for perimenopausal syndrome

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